A switch mechanism for G ss gamma activation of I-KACh

G protein-gated inwardly rectifying potassium (GIRK) channels are a family of K+-selective ion channels that slow the firing rate of neurons and cardi ac myocytes. GIRK channels are directly bound and activated by the G protei n G beta gamma subunit. As heterotetramers, they comprise the GIRK1 and the GIRK2, -8, or -4 subunits. Here we show that GIRK1 but not the GIRK4 subun it is phosphorylated when heterologously expressed. We found also that phos phatase PP2A dephosphorylation of a protein in the excised patch abrogates channel activation by G beta gamma. Experiments with the truncated molecule demonstrated that the GIRK1 C-terminal is critical for both channel phosph orylation and channel regulation by protein phosphorylation, but the critic al phosphorylation sites were not located on the C terminus. These data pro vide evidence for a novel switch mechanism in which protein phosphorylation enables G beta gamma gating of the channel complex.